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Women who inherit a deleterious mutation in BRCA1[27,28] or BRCA2[29] have an increased lifetime risk of breast cancer (which occurs at a younger age), ovarian cancer, and possibly colon cancer. Deleterious BRCA2 mutations are less common than BRCA1[30] mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.[31]

Factors Associated With Increased Risk of Breast Cancer

Hormone therapy

Exogenous hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk in 1997.[32]

The Heart and Estrogen/Progestin Replacement Study published in 2002 [33] included an open-label follow-up of a randomized controlled trial (RCT) of estrogen and progestin therapy in 2,763 women (mean age, 67 years) who had coronary heart disease. After a mean follow-up of 6.8 years, the relative risk [RR] for breast cancer was 1.27 (95% confidence interval [CI], 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women's Health Initiative (WHI) study.

The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits.[34]

The randomized trial component of the WHI investigated the effect of hormones and dietary interventions on breast cancer risk.[34] Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.02–1.50), consistent with prior reports from observational studies. The trial was terminated early because overall health risks, including cardiovascular disease and thrombotic events, exceeded benefit.[34] HT was also associated with a higher percentage of abnormal mammograms.[35] The excess risk was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases.[36] Extended follow-up (mean follow-up of 11 years) of these women showed higher breast cancer-specific mortality for the HT group compared with those randomly assigned to receive placebo (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.0–4.04; P = .049).